by Stephen R D
Johnston, Masakazu Toi, Joyce O'Shaughnessy, Priya Rastogi, Mario Campone,
Patrick Neven, Chiun-Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan
Cicin, Sara M Tolaney, Matthew P Goetz, Hope S Rugo, Elzbieta Senkus, Laura
Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz,
Belen San Antonio, Valérie André, Nadia Harbeck, Miguel Martin, monarchE
Committee Members
The Lancet Oncology: VOLUME 24,
ISSUE 1, P77-90, JANUARY 2023
Background
Adjuvant
abemaciclib plus endocrine therapy previously showed a significant improvement
in invasive disease-free survival and distant relapse-free survival in hormone
receptor-positive, human epidermal growth factor receptor 2 (HER2; also known
as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we
report updated results from an interim analysis to assess overall survival as
well as invasive disease-free survival and distant relapse-free survival with
additional follow-up.
Methods
In monarchE, an
open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had
hormone receptor-positive, HER2-negative, node-positive, early breast cancer at
a high risk of recurrence with an Eastern Cooperative Oncology Group
performance status of 0 or 1 were recruited from 603 sites including hospitals
and academic and community centres in 38 countries. Patients were randomly
assigned (1:1) by means of an interactive web-based response system (block size
of 4), stratified by previous chemotherapy, menopausal status, and region, to
receive standard-of-care endocrine therapy of physician's choice for up to 10
years with or without abemaciclib 150 mg orally twice a day for 2 years
(treatment period). All therapies were administered in an open-label manner
without masking. High-risk disease was defined as either four or more positive
axillary lymph nodes, or between one and three positive axillary lymph nodes
and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A
smaller group of patients were enrolled with between one and three positive
axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature
(cohort 2). This was a prespecified overall survival interim analysis planned to
occur 2 years after the primary outcome analysis for invasive disease-free
survival. Efficacy was assessed in the intention-to-treat population. Safety
was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is
ongoing.
Findings
Between July 17,
2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 [99·4%] were
women and 36 [0·6%] were men). 2808 were assigned to receive abemaciclib plus
endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At
a median follow-up of 42 months (IQR 37–47), median invasive disease-free
survival was not reached in either group and the invasive disease-free survival
benefit previously reported was sustained: HR 0·664 (95% CI 0·578–0·762,
nominal p<0·0001). At 4 years, the absolute difference in invasive
disease-free survival between the groups was 6·4% (85·8% [95% CI 84·2–87·3] in
the abemaciclib plus endocrine therapy group vs 79·4% [77·5–81·1] in
the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib
plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in
the endocrine therapy alone group (HR 0·929, 95% CI 0·748–1·153; p=0·50). The
most common grade 3–4 adverse events were neutropenia (in 548 [19·6%] of 2791
patients receiving abemaciclib plus endocrine therapy vs 24 [0·9%] of
2800 patients in the endocrine therapy alone group), leukopenia (318
[11·4%] vs 11 [0·4%]), and diarrhoea (218 [7·8%] vs six
[0·2%]). Serious adverse events occurred in 433 (15·5%) of 2791 patients
receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800
receiving endocrine therapy. There were two treatment-related deaths in the
abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none
in the endocrine therapy alone group.
Interpretation
Adjuvant
abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the
completion of treatment with an absolute increase at 4 years, further
supporting the use of abemaciclib in patients with high-risk hormone receptor-positive,
HER2-negative early breast cancer. Further follow-up is needed to establish
whether overall survival can be improved with abemaciclib plus endocrine
therapy in these patients.
